GSBS Dissertations and Theses

Approval Date

10-21-2016

Document Type

Doctoral Dissertation

Academic Program

Cancer Biology

Department

Molecular, Cell and Cancer Biology Department

First Thesis Advisor

Junhao Mao, Ph.D.

Keywords

Gastrointestinal Tract, Neoplastic Cell Transformation, Mesenchymal Stromal Cells, Phosphoproteins, Signal Transducing Adaptor Proteins, Transcription Factors, Protein-Serine-Threonine Kinases, Hippo Pathway, Mammals

Subjects

Dissertations, UMMS; Gastrointestinal Tract; Cell Transformation, Neoplastic; Mesenchymal Stromal Cells; Phosphoproteins; Adaptor Proteins, Signal Transducing; Transcription Factors; Protein-Serine-Threonine Kinases

Abstract

In cancer, aberrant activation of developmental signaling pathways such as the Hippo Pathway has been shown to drive proliferation and invasion of cancer cells. Therefore, understanding the normal function of the Hippo Pathway during embryonic development can provide critical insight into how aberrant activity contributes to tumorigenesis. This dissertation explores the role of the Hippo Pathway members YAP and TAZ in gastrointestinal (GI) development and tumorigenesis. I use mouse genetics to systematically dissect the roles of YAP/TAZ in the endoderm-derived gastrointestinal epithelia and mesoderm-derived gastrointestinal mesenchyme during mammalian development. In the GI epithelium, I demonstrate that YAP/TAZ are dispensable for development and homeostasis. However, YAP/TAZ are required for Wnt pathway-driven tumorigenesis. I find that YAP/TAZ are direct transcriptional targets of Wnt/TCF4 signaling. In the GI mesenchyme, I describe a previously unknown requirement for YAP/TAZ activity during mammalian GI development. YAP/TAZ are involved in normal GI mesenchymal differentiation and function as transcriptional co-repressors in a progenitor cell population. In this way, YAP/TAZ act as molecular gatekeepers prior to Hedgehog-mediated differentiation into smooth muscle cells. This work unveils a previously unknown requirement for Hippo pathway signaling in the mammalian GI tract and a novel mechanism wherein YAP/TAZ function as transcriptional co-repressors to maintain a mesenchymal progenitor cell population.

DOI

10.13028/M24K54

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Thursday, November 15, 2018

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